title: Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression.
abstract: Amyotrophic lateral sclerosis is a typically rapidly progressive neurodegenerative disorder affecting motor neurons leading to progressive muscle paralysis and death, usually from respiratory failure, in 3-5 years. Some patients have slow disease progression and prolonged survival, but the underlying mechanisms remain poorly understood. Riluzole, the only approved treatment, only modestly prolongs survival and has no effect on muscle function. In the early phase of the disease, motor neuron loss is initially compensated for by collateral reinnervation, but over time this compensation fails, leading to progressive muscle wasting. The crucial role of muscle histone deacetylase 4 and its regulator microRNA-206 in compensatory reinnervation and disease progression was recently suggested in a mouse model of amyotrophic lateral sclerosis (transgenic mice carrying human mutations in the superoxide dismutase gene). Here, we sought to investigate whether the microRNA-206-histone deacetylase 4 pathway plays a role in muscle compensatory reinnervation in patients with amyotrophic lateral sclerosis and thus contributes to disease outcome differences. We studied muscle reinnervation using high-resolution confocal imaging of neuromuscular junctions in muscle samples obtained from 11 patients with amyotrophic lateral sclerosis, including five long-term survivors. We showed that the proportion of reinnervated neuromuscular junctions was significantly higher in long-term survivors than in patients with rapidly progressive disease. We analysed the expression of muscle candidate genes involved in the reinnervation process and showed that histone deacetylase 4 upregulation was significantly greater in patients with rapidly progressive disease and was negatively correlated with the extent of muscle reinnervation and functional outcome. Conversely, the proposed regulator of histone deacetylase 4, microRNA-206, was upregulated in both patient groups, but did not correlate with disease progression or reinnervation. We conclude that muscle expression of histone deacetylase 4 may be a key factor for muscle reinnervation and disease progression in patients with amyotrophic lateral sclerosis. Specific histone deacetylase 4 inhibitors may then constitute a therapeutic approach to enhancing motor performance and slowing disease progression in amyotrophic lateral sclerosis.
authors.affiliation: APHP, Hôpital Pitié-Salpêtrière, Département de Neurologie, Centre référent SLA, Paris Cedex 13, France. gaelle.bruneteau@psl.aphp.fr
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Bruneteau
authors.forename: Thomas
authors.initials: T
authors.lastname: Simonet
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bauché
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mandjee
authors.forename: Edoardo
authors.initials: E
authors.lastname: Malfatti
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Girard
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Tanguy
authors.forename: Anthony
authors.initials: A
authors.lastname: Behin
authors.forename: Frédéric
authors.initials: F
authors.lastname: Khiami
authors.forename: Elhadi
authors.initials: E
authors.lastname: Sariali
authors.forename: Caroline
authors.initials: C
authors.lastname: Hell-Remy
authors.forename: François
authors.initials: F
authors.lastname: Salachas
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Pradat
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Fournier
authors.forename: Lucette
authors.initials: L
authors.lastname: Lacomblez
authors.forename: Jeanine
authors.initials: J
authors.lastname: Koenig
authors.forename: Norma Beatriz
authors.initials: NB
authors.lastname: Romero
authors.forename: Bertrand
authors.initials: B
authors.lastname: Fontaine
authors.forename: Vincent
authors.initials: V
authors.lastname: Meininger
authors.forename: Laurent
authors.initials: L
authors.lastname: Schaeffer
authors.forename: Daniel
authors.initials: D
authors.lastname: Hantaï
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000294:innervation* / Q000378:metabolism / Q000473:pathology; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D017741:Survivors; D015854:Up-Regulation
chemical_list: C546087:MIRN206 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; C400300:HDAC4 protein, human; D006655:Histone Deacetylases
keywords: ALS; HDAC; motor neuron; neuromuscular junction; reinnervation